Alzheimer's disease (AD), the third most costly disease in the United States after cardiac disease and cancer, has shown an increase in incidence recently, moving from 7th to 5th as a leading cause of death among the elderly. Currently available medical strategies treat the symptoms rather than address the underlying processes responsible for the progressive decline in cognitive function seen in AD patients. However, results from both clinical and basic science research suggest that antidiabetic agents (e.g., thiazolidinediones - TZDs) may be beneficial in the treatment of AD, and a few human and animal studies have shown that use of rosiglitazone (a TZD) can improve memory and lead to cognitive improvements. These results appear to provide compelling preliminary evidence to support the use of antidiabetic drugs to combat the cognitive impairment associated with AD. However, little is known about the underlying molecular mechanisms, or about the identity of the CNS targets of TZDs. Some of the proposed beneficial effects of TZDs include reestablishment of insulin sensitivity and associated peripheral and/or CNS glucose utilization, along with reductions in inflammatory cytokines, Ab1-42 deposits, microglial activation, and intracellular Ca2+ levels. Given that Ca2+ dysregulation is considered a hallmark of brain aging and AD, and is also present in animal models of diabetes, we propose that some Ca2+ biomarkers of brain aging may be targets for intervention with TZDs. Using electrophysiological, molecular and Ca2+ imaging techniques along with a team of qualified scientists, this project will test the overall hypothesis that some TZDs can improve cognitive status in aged animals, by reducing key biomarkers of brain aging and neurodegeneration in the hippocampus. We will determine the molecular bases underlying the potential use of TZDs for the treatment of AD by the following Specific Aims: 1) to test the hypothesis that TZDs act as neuroprotective agents by normalizing Ca2+ levels within neurons and/or glial cells; and 2) to test the prediction that in vivo TZD treatment can improve cognition in aged animals and restore Ca2+ homeostasis. Results form our studies may provide support for the therapeutic application of TZDs in preventing/retarding the cognitive decline seen in AD. Furthermore, these studies will contribute to future drug discovery efforts to generate new TZD-derived or similar drugs for the treatment of AD. [unreadable] [unreadable] [unreadable]